Reversible histone acetylation is under the control of opposing enzymatic activities of two categories of enzymes: histone deacetylases (HDACs) and histone acetyltransferases (HATs). Deacetylation of lysine residues on N-terminal tails of histones by HDACs is generally associated with transcriptional silencing, whereas acetylation of the same lysine residues is associated with transcriptional activation. In addition to histones, a rapidly growing number of other non-histone proteins undergo the post-translational modification of acetylation on lysine residues. An example of some of these proteins include HMG-14 and 17, HMGI(Y), p53, E2F1, NF-κB, and the HIV-1 Tat protein. HDACs are separated into three distinct classes based on their homology to yeast transcriptional repressors. Class I and Class II deacetylases are homologues of the Rpd3p and Hda1p proteins, respectively. Class III HDACs are defined based on their homology to the yeast transcriptional repressor, Sir2p.
The Silent Information Regulator (SIR) gene family was initially identified based on its role in the regulation of gene expression at the HM loci in S. cerevisiae. Later studies further defined the role of SIR proteins in transcriptional silencing at a number of additional loci in the yeast genome, including telomeres, rDNA locus, and at sites of DNA damage. Silencing at the telomeres and the HM loci, is mediated by a multiprotein complex which includes Sir2p, Sir3p and Sir4p, with Sir1p being involved in silencing at the HM loci only. Interestingly, silencing and repression of recombination at the rDNA locus is achieved by Sir2p in association with the RENT complex, containing Net1, Nan1 and cdc14, and has been associated with aging in S. cerevisiae. The recent discovery that SIR2 encodes an NAD-dependent histone deacetylase has validated the long held suspicion that this protein regulated the level of histone acetylation.
The SIR2 family of genes is conserved from archaebacteria to eukaryotes. In S. cerevisiae, this family consist of Sir2 and four closely related genes (HST1-4). Whereas Sir2p and HST1p are localized primarily in the nucleus, Hst2p is exclusively cytoplasmic. Humans have seven proteins with homology to the S. cerevisiea Sir2p, which have been named Sirtuins or SIRTs. Human SIRT1 and mouse Sir2α, which are most closely homologous to Sir2p and HST1p, exhibit protein deacetylase activity with specificity for the transcription factor protein p53. Deacetylation of p53 by SIRT1 suppresses p53-dependent apoptosis in response to DNA damage. The human SIRT2 protein, which is most closely related to Hst2p, is also localized in the cytoplasm. Interestingly, both SIRT2 and Hst2p regulate rDNA and telomeric silencing indirectly from their cytoplasmic location.
The microtubule network is formed by the polymerization of α/β tubulin heterodimers and plays an important role in the regulation of cell shape, intracellular transport, cell motility, and cell division. α and β tubulin sub-units are subject to numerous post translational modifications including tyrosination, phosphorylation, polyglutamylation, polyglycylation and acetylation. Tubulin represents one of the major acetylated cytoplasmic proteins. Acetylation of tubulin takes place on lysine-40 of α-tubulin, which based on the crystal structure of the tubulin heterodimer, is predicted to lie within the luminal side of the polymerized microtubule.
A variety of physiological signals have been reported to modulate the level of tubulin acetylation. This includes the anticancer drug paclitaxel, as well as association of MAP1 and 2C, tau, and the herpes simplex virus encoded protein VP22. Similarly, microtubules associated with stable structures, such as cilia, contain relatively hyperacetylated α-tubulin. These observations have supported the notion that stabilized microtubules become hyperacetylated. However, the enzymes responsible for the reversible acetylation of tubulin have not been identified. This lack of reagents has precluded a thorough analysis of the biological role of tubulin acetylation in microtubule dynamics, stability and physiological functions of the cytoskeleton.
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